CA2130265A1 - Dihydropyrimidine nucleosides with antiviral properties - Google Patents

Abstract

Pharmaceutical compounds of general formula (I) have been prepared and non-toxic pharmaceutically acceptable salts thereof, wherein R1 is a halogen substituent; R2 is a member selected from the group consisting of alkoxy, hydroxy and azido; and X-Y is a member selected from the group consisting of CH(N3)-CH2, CH(F)-CH2 and CH = CH. Halogen denotes an iodo, bromo, chloro and fluoro atom. Alkoxy denotes a straight or branched chain moiety having 1-16 carbon atoms. Compounds of formula (I) can exist as the (5R, 6R), (5S, 6S), (5R, 6S) and (5S, 6R) diastereomers which differ in configuration at positions C-5 and C-6. These compounds exhibit anti-human immunodeficiency virus activity (anti-HIV) and are useful in the treatment of acquired immunodeficiency syndrom (AIDS) and AIDS-related complex.

Description

~094/1~1 PCT/CA93/00553 2~3~2~

DIHYDROPYRIMIDINE NUCLEOSIDES ~ITH ANTIVIRAL PROPERTIES

FIELD OF THE INVENTION
,.
The present invention relates to pharmaceutical : : compounds. More particularly, the invention provides new unnatural 5,6-dihydropyrimidine nucleoside derivatives, or non- toxic pharmaceutically acceptable salts thereof, hav-ing useful physlological antiviral effects, particularly ~ anti-human immunodeficiency virus (anti-HIV) properties :~: which are useful in the treatment o~ acquired immuno-deficiency syndrome (AID5) and AIDS-related complex. The invention relates to such compounds and compositions there-of, and to processes for making and using them.
~:
:~ :: BACKGROUND OF~THE INVEN_ION
: ~ Human immunodeficiency virus-1 reverse tran-~: scriptase (HIV-1 ~T) plays an important role in the life cycle of the virus and has been a major target for the ~: :
design of drugs to combat AIDS: One class of HIV-1 RT
inhibitors are pyrimidine nusleoside analogs such as 3'~-azido-3'-deoxythymidine ~ZT), 3'-fluoro-3'-: deoxythymidine (~FT) and 2'i3'-didehydro-2',3'-dideoxythymidine (d4T). These compounds are conve~ted intotheix triphosphates~by cellular enzymes, the triphosphates are then recognized by HIV-1 RT as substrates. The corres-ponding nucleoside monophosphate moiety is inccrporated ~; into deoxyribonucleic acid (DNA) chains. Since these , ~ analogs lack a 3'-hydroxyl group, this incorporati~n leads to DNA chain termination. Although A~T appears to be temporarily effective in decreasing mortality and morbidity in some patients ~with AIDS, or AIDS-related complex, bone marrow toxicity and anemia are very severe [see the Medical WOg411~1 PCT/CA93/0~553 ~5 -2-Letter, 28 , 107 (1986)]. Frequently administered high doses of AZT must be used to maintain a therapeutic drug level due to its short biological half-life of one hour ~see D.D. Richman, M.A. Fischl, M.H. Grieco, M.S.
Gottlieb, P.A. Volberding, O.L. Laskin, J.M. Leedom, J.
Groopman, D. Mildvan, M.S. Hirsch, G.G. Jackson, D . T .
Durack and S. Nusinoff-Lehrman, N. Engl. J. Med., 317, ~92 (1987)] which is attributed to its rapid metabolism to the inactive 5'-0-glucuronide ~GAZT) and the highly toxic 3~- amino-3'-deoxythymidine (AMT) [see E.M. Cretton, M.-Y.
Xie, R.J. Bevan, N.M. Goudgoan, R.P. Schinazi and J.-P.
Sommadossi, Mol. Pharmacol., 39 , 258 ~1991)]. Since AZT
does not penetrate into brain tissue from the cerebral spinal fluid, it does not effectively suppress viral ; replication in the brain and it is believed that the HIV
replicates more rapidly in the central nervous system ~(CNS), the CNS serving as a reservoir for the virus in the body.
~ ~ , A correlation between lipophilicity, membrane ; ~ permeability and~CNS penetration has long been established [~see~C. Hansch,~A.R.~ Stewart, S.M. Anderson and D. Bentley, J.~Med. Chem., ~ 11 , 1 (1968); D.P. Hall and C.G. Zubrod, 25 ~Ann. Rev. Pharmacol~., 2 , 109 ~1962); W.H. Oldendorf, Proc. Soc. Exp. Biol. Med., 147 , 813 ~1974)~. The pophilicity of a compound can be described as the partitlon coefficient (P) of~ a drug between 1-octanol (lipid phase) and aqueous buffer at a pH of 7. It has been reported that the partition coefficients for AZT, FT and ~ d4T arè 0.964, 0.529 and 0.154, respectively ~see E.J.
;~ Li~n, H. Gao and H. Prabhaker, J. Pharm. Sci., 80 , 517 ~(1991)]. Although AZT is the most lipophilic, it is neither lipophilic nor hydrophilic since it partitions ~-~ 35 almost equally (P = O.964). Several studies to design more lipophilic compounds, and hence their ability to penetrate into the CNS across the blood-brain-barrier (BBB) have not , .

W09411~1 PCT/CA93/00553 resulted so far in compounds with an acceptable therapeutic potency.
Although a number of 5,6-dihydrothymidine analogs of the physiological nucleoside thymidine are known (see A.G. Samuel, H.B. Mereyala and K.N. Ganesh, Nucleosides &
Nucleotides, ll , 49 (1992); R. Teoule, B. Fouque and J.
Cadet, Nucl. Acid Res., 2 , 487 (1975); G. Bernardinelli, R. Benhamza and J.M. Tronchet, Acta Cryst. C45 , 1917 (l989)] these analogs act as competitive inhibitors of ~; . th~midine kinase at low concentrations ~see B. Fouque and R, Teoule, Chemotherapy, 20 , 221 (1974)]. Since these analogs do not lnhi~it reverse transcriptase, they are in-effective in the treatment of AIDS or AIDS-related complex.
It has now been discovered that the introduction of a halogen atom in position 5 in conjunction with an alkoxy, hydroxy~or azido substituent in position 6 increase 2~0~ 1ipophiliclty~thereby resulting in an increased ability to p~netrate into the CNS.~ Such compounds exhibit anti-human ~mmunodeficiency ~vlrus (anti-HIV) activity and may al30 be ; ~~ useful to treat other clinical conditions such as hepatitis B~vlral lnfectlons~and other~viral infections.
` ~ ~ In ;addition such compounds have a longer blological half-life allowing for a longer duration of ac;tlon and they exhibit an increasing drug s~ability and a decreasing toxicity:. Alternatively, such compounds may serve~ as pro-drugs, ~since a reducing agent (such as glutathione in vivo) would regenérate the 5j6-olefinic bond releasing AZT, FT or d4T.

DETAILED DESCRIPTION OF THE INVENTION

.~ 35 The present inventlon relates to new 5,6-dihydro-pyrimidine derivatives and non-toxic, pharmaceutically acceptable salts thereof (as well as pharmaceutical WO94/1~1 PCT/CA93/00553 . .:
Z~3l)265 compositions containing them).
The new compounds according to the present invention have the general formula:

o M~ ll R1~--N_H
R7~N~Ci I i HO~o jJ

~ ~ : x - y ~: wherèin: ~
Rl is::a halogen;
: R2~is:~a~:hydroxy, alkoxy group or azido; and ~ X-Y lS~ a~member selected ~rom the group CH=CH, C~(N3):-CH2 or: CH(F)-CH2 as well as the non-toxic, pharmaceuticalIy~accepta~le salts thereof.
The term~"halogen" as used herein means fluorine, chlor1ne, bromine~or~iodine.
2:5~ The term ~"~alkoxy:~" as used herein means sub-: : s:titue~ts of straight and branched chain aliphatic alcohols having from 1 to ~ 6~carbon atoms.
~ , Compounds:of formula (I) can exist as one of four possLb1e diastereomer~s wherein: Rl and R2 have the mean-~: 30 ings given above since an asymmetric carbon is respectively present at the C-5 and C-6 positions.
~:~ : The term 'Idiastereomer~' means the (5R,6R), : : (5S,6S), (5R,6S)~or (5S,6R) conflguration.
: The 5-halo-6-alkoxy-5, 6-dihydrothymidine ' wOg4~ PCTICAg3/00553 -5- 213026~
. ~
derivatives are prepared by reacting a thymidine analog of the formula:
o Me~H
~0 I (II) HO~O~
X Y

wherein X-Y is a member selected from the group consis~ing : of CH(N3)-CH2, CH(F)-CH2 and CH-CH with an ~:: electrophilic source of halogen of the formula:

R1-Z (III) wherein R1 is an~iodo,:bromo, chloro or fluoro atom and Z
S a member lndependently.selected from the group consist-ing of iodo, bromo and chloro, in the presence of an alkyl . 20~: alcohol of the~formula:

R2-H ~IV~

: wherein~R2 is an alkoxy group wherein the alkyl moiety is 25~ a~ straight: or:branched aliphatic alkyl chain having from 1 :to 16 carbon atoms, :allowing the reaction to sccur in the temperature range o~ -78C to 25C, preferably in the 0C
:to ;25C range, to convert to 5-halo-6-alkoxy-5, 6-~: : : dihydrothymidine diastereomers of the formula:
:: ~

Me ll ' R~N_H
~N~O ~ I ) ~ ~ HO~o~
:: : 3 5 : x Y
: wherein R1, R2 and X-Y are as defined above. The reactions are allowed to take place in inert organic `

WO9411~1 PCT/CA93/00553 Z~30~65 -6-solvents such as tetrahydrofuran, dioxane or dimethoxy-ethane when the alkyl alcohol of formula (IV) is a solid.
Alternativelyl compounds of formula (I) can also be prepared by reacting a thymidine analog of formula (II) wherein X-Y is as defined above, with an electrophilic source of halogen of the formula:
o ~: : 1 0 (V) : : O

wherein Rl is a member selected from the group consisting : o.f iodo, bromo and chloro, in the presence of an alkyl alcohol of formula (IV~:wherein R2 is as defined as above and glacial acetic :acid, allowing the reaction to occur at 2SC to: convert to~ 5-halo-6-alkoxy-5,6-dihydrothymidine 20~ derivatives of the formula (I) wherein Rl, R2 and X-Y
ar~ as defined as~ above.: These reactions are allowed to take~ place in lnert organic solvents such as dimethoxy-ethane, dioxane or tetrahydrofuran (preferably dimethoxy-ethane).
. , 25;~ The 5-halo-6-azldo-5,6-dihydrothymidine derlvative~s are prepared by reacting a thymidine analog of :the~:formula: (II) -wherein X-Y is as defined as above, with an electrophilic source of halogen :of the formula ~V) :
wherein Rl is as defined above, in an inert organic solvent such as ~ dimethoxyethane, dioxane or : tetrahydrofuran,. preferably dimethoxyethane, and an alkali metal azide of the formula (VI):

::

: 35 wherein R2 is an azldo group and M is selected from a group consisting of sodium, lithium and potassium, prefer-~94/1~l PCTICA93/00553 Z13~265 ably sodium, in a water solvent, allowing the reaction to occur in the -5C to 25C range to convert to 5-halo-6-azido-5,6- dihydrothymidine diastereomers of the formula:
M

R ~ N ~ O (I) 10` ~tO~o~J
x Y
wherein Rl is a member selec~ed from the group consisting o~ iodo, bromo and chloro, R2 is an azido substltuent and X-Y is as defined above.
15The 5-halo-6-hydroxy-5,6-dihydrothymidine deriva-tives are prepared by reacting a thymidine analog of ~: ~ formula (II~ wherein X-Y is as defined above, with an electrophilic source of halogen of the formula (V) wherein R1 is as defined above, in water as a solvent, allowing ;~ 20 the reaction to occur at OC to convert ~o 5-halo-6 : hydroxy-5,6-dihydrothymidine diastereomers of the formula (I) whereln R1 is a member selected from the group con-sisting of iodo, bromo and chloro, R2 is a hydroxyl sub-stltuent and X-Y ls as defined above.
~2:5~More particularly, the compounds listed in the Examples and ln Ta~le I, II, and III have been prepared, and through testing, have been found to have anti-human immunodeficiency virus properties (Table IV).
~: : Suitable~ pharmaceutically acceptable phosphate : 30 forms of these compounds include the 5'-0-monophosphate, 5'-0- diphosphate and 5'-0-triphosphate derivatives.
These compounds can be administered either parentally, as by in~ection, or orally. As a liquid : ~ carrier, a carx;ier such as water or polyethylene glycol, or : 35 other physiologically acceptable solvents or dispersing liquids can be used. For oral administration, either solid or liquid carriers may be used. One commonly used solid W094/l~l PCT/CA93fO0553 2~302~ -8- ~
.. ' , :
carrier is gum acacia, but others are also suitable. An operative dosage range is between about 0.01 and 200 mg/kg, preferably between 0.1 and 20 mg/kg.
The following non-limitative examples illustrate some selective methods for producing the compounds accord-ing to the present invention, as well as comparative data illustrating the anti-human immunodeficiency virus ~anti-HIV) effect of representative compounds according to the present invention.
The starting materials for the preparation of compounds of formula (I), viz the thymidine analogs of formula (II), the electrophilic forms of.halogen of formula (III)~ and formula (V), the alkyl alcohols of formula (IV), and azides of formula (VI) are either known or are conven-ient~ly `prepared from~known starting materials from methods known per se.
: ~
The following examples are given for the purpose ;20~ of lllustrating the~present invention: -; Preparation of~5-bromo-6-methoxy-5,6-dihydro-3'-25~ ~azldo-3'-deoxythymidlne~;
SchematîcforE~mPie o : ~ o~ M o Me~N--H ~ ~ ~ ; Me ~JI~ Bf .. ~N-H
3 0 ~ ~ ~N~O; MeO~N oMeo~r~bo ¦ Br2 MeQH ~ i l :

IV); HO~ ~

N3 N ::

~ A freshly prepared solution of methyl hypobromite (bromine in methanol)~ was added dropwise to a solution of 3'-azido-3'-deoxyth~mi~dine-(0.2 g, 0.75 mmol) in methanol : ~

~.

: .

~094/1~l PCT/CA93/00553 9 2~3~

(10 mL) at 25OC with stlrring until the light yellow color of the reaction mixture persisted. The reaction was allow-ed to proceed at 25C for 20 min prior to neutralization topH 6 using a solution of methanolic sodium hydroxide.
Removal of the solvent in vacuo, dissolution of the residue in methano~ (5 mL), adsorption onto silica gel (1 g), removal of the solvent in vacuo, and application of this material to the top of a silica gel column (Merck 7734, 100-200 ~M particle size) followed by elution with chloro-form-methanol (95:5, v~v~ afforded a mixture of ~he diastereomers K-1 and K-2 (0.225 g, 79%) as a viscous oil.
Analysis found: C, 34.40; H, i4.27; N, 17~85.
:
CllHl6BrN5O5- 1/2 H2O requires: C, 34.12, H, 4.42; N, 18.08. The two diastereomers (5R,6R)-5- bromo-6-methoxy-5,6-dihydro-3'-azido-3'-deoxythymidine ~K-1) and (5S,6S)-5-bromo-6-methoxy-5,6-dihydro-3'-azido-3'-deoxythymidine (K-2) were separated using Whatman PLK5 2~0~ silica gel~ plates ~(1 mM thickness) using chloroform-mëthanol (95.5, v/v)~as devel.opment solvent.
Diastereomer K-1: ~a]D25= +71.7(c 0.0030, MeOH); Rf 0:.61: oil; yield (60 mg, 21%); lH MMR
(CDCl3) ~ 1.96 (s, 3H, CH3j, 2.32 and 2.68 (two m, lH
each, H-2'),.: 3.46~(s, 3H, OCH33, 3.80 (m, lH, H-5'), 3.94 ~: :
m, 2H, H-4', H-5H), 4.34 (m, lH, H-3'), 4.95 (s, lH, H-6), : 5.90 ~(d, J1~,2:~:=6.0 Hz, lH, H~ , 8.64 (s, lH, NH, ~exchanges with deuterium oxide): 13C NMR (CDCl3) 22.82 (CH3), 37.04 (C-2'), 53.~21 (C-5), 57.41 (OCH3), 60.06 (C-3'), 62:.12 (C-5'), 8~.02 (C-4'), 86.66 (C~
~ 89.16 (C-6), 150.58 (C-2 C=0), 167.10 (C-4 C=0).
:Diastereomer K-2: [a]D25= -43 3O (c 0.0021, ~ MeOH); Rf 0.63; oil; yield ~0.148 gi 52%); 1H NMR
: : (CDCl3) ~ 1.98 (s, 3H, CH3), 2.26 and 2.96 (m, 2H, H-2'), 3.60 (s, 3H, OCX3), 2.76 (m, lH, H-5'), 2.94 (m, : :lH, H-5"), 4.02 (m, lH, H-4'), 4.52 (m, lH,H-3l), 4.59 (s, : lH, H-6), 5.27 (d, J1~,2~=6.0 Hz, lH, H-1'), 8.53 WO94/1~ , . PCT/CA93/00553 .._ 2~3026S - 1 o-~s, lH, NH, exchanges with deuteriu~. oxide); 13C NMR
(CDCl3) ~ 22.66 (CH3), 35.01 (C-2'), 53.34 (C-5), 57.15 ~OCH3), 61.48 (C-3') 62.86 (C-5'), 85.05 (C-4'), 92.56 (C-1'), 95.27 (C-6), 150.51 (C-2 C=0), 166.83 (C-4 C=0).

Example 2 10Utilizing the general procedure of Example 1 and starting from the appropriately substituted compounds of : ~ the formula (II), of formula (III) and of formula (IV), as :: represented in the schematic for Example 2, the following compounds of the~ formula~I) are prepared:
15 .Schematic for Example 2 Schema~c for ExamDle 2 Ue~--H :~ ~ H~, ~H . H.~

HO ¦ +: R1-Z ~+~ ~ R2--H
HO~ X--`( (SR 6R) ~SS.6S) : 25~ ::

:~ :
: ~; 30 WO 94/14831 ~ 30Z65 PCT/CAg3/005~3 ! ` ., . ; . . .

¦ r~ Ir~ ~ I i I O ~
~ ~ C O O CC, 5 C O r~; '~ '' I J

_ ~11^1 ~ OIt- Q IJ'l r- ~ o ~i O
~ r ~ r-~ r~7r~ ~ r~ r~
ll O O O _ O O O O O O O Q) _ O O O O O O O O O O O I~
O o o o o o o o o o o o ~, r~
L~ O O O O O O O O O O O
r~J O ~o r~ o r~ ~D ~ ~ o O
._ r~ r-r~ r~ ~ rr~ r r- ~r~
_ t I + t + ~ + ~ ~ ~ I ~O
rD~n ~ r~ -- ~ c o o r- ~ -- ~ r~
r,o ~o r- ~ ~ rDr ~ rD ~r~ D C
~ ~ o o o o o o o o o o o o o ~
a' r~ r~ r~ ~ ~ r~ r~
1~3 ~ ~ p p r~- _r~ r~
8 I_~,O X ~: Z Z Z Z Z Z ~ -- I ' O
;~ 0~; z 7. _ ~ ~ 5 ~i G ~
~ I U~ ! ~!
U ~ ,X ~ ~ r~ ~ _ U C) .. ~ r~ r~
r~ I r~ v ' ~ ^ ~ ' r~ ~ ~ v . ~: O O ~ b 1~ _ :~ ~L ~o ....... ,: o o o ,c U C~~~ Z 7 --~ ~ ~ ~ ~ ~ ~ ~ ~ h ~ ~ ~
CL ~/ ~0~ ~r !~ al ~ ~ o m t~ Cl c ~ c o~ ~ ,X C/~ O--I ~ r-7 ~ L~l , 1 ~ i ~ r~ ~L'~ ~ r- co ~.~ ' ^ :~: ~ ~ I ,c I ~ ,~ ~ ~ x ~ ~: 8 .
a ~ ~ ~ b ~ b~ b b ~

u ~ _ _ - ~ N ~ . r~ ,~ _~
~ : 1 O r7 r-~ --Nl ~r'~ -I O '' ~ ' ~5 --V ~
~: ~r~ "~ r~ 0 0 ~ '.~ ~

~ i~i r~ r~i I O h r ~ ~, i~
T~ ~ i i~ r ' o ,~ ~ ~n _. ~ >, r r~ '~` ~ r~
) r~i r~~ D OO ri G O i~ .
~, l ~ u, ~ ' ~,~ r, r, ~n . ~ L; ~ ~ ~i ~n I O ~ -~ ~ ~
~i ~i L~ I ~ ~ ~i ~ i Ln r3 ~ X ;~ (~
. ~ X V O .~ ~) L'l "~ - C _i l : Y ~ 8 ` F ~ > ~ ~ r, ~D ~ ~D I ~r;i I ~D ~ ~ tO ~D ~ ~ ~ ~ ~
~ 8 ~ ~ ~ ~ 8 ~ b ~
~ D y i r, D ~ D ~ ~' r~i ~ L'~ L i L--l L iL'~L i ~ IJ~ iri L i Lri L'i L'i O $
_~ ~ ~ r~ , ~ v i.L
~ ~ . . . . . . iJ ~i I !
ri L '~r- L i i.''l ri L'l ' ' L i '.n ~

STITUTE SHiE~;ET

WO94/1~1 PCTICA93/00~53 .

2 ~ 3 ~ 2 6 5 -12-Example 3 Preparation of 5-chloro-6-ethoxy-5,6-dihydro-3'-azido-3'-deoxythymidine.
Chlorlne gas (4.7 g) was bubbled slowly into a suspension of 3'-azido-3'-deoxythymidine (10 g, 37.4 mmol) in 98% ethano~ (500 mL) at 0C with stirring until the light yellow-green color of the resulting solution persist-ed. The pH of this solution was adjusted to 6.5 using a solution of sodium hydroxide in ethanol and the mixture was filtered. Removal of the solvent from the filtrate in vacuo and separation of the residue obtained by elution from a silica gel column using chloroform-methanol (97:3, ; v/v) as eluent gave (SS,6S)-5- chloro-6-ethoxy-5,6-dihydro-3~'-azido-3'-deoxythymldine (K-17), (5R,6R)-5-chloro-6-ethoxy-5,6-dihydro-3'-azido-3'-deoxythymidine (K-16), and (5S,6R)-5-chloro-6-ethoxy-5,6-dihydro-3'-azido-3'-deoxy-thymidine ~K-18),~;~respectively. Analysis found: C, 41.62;
H, 5.20; N,~ 19~.~81. ~ C12H18ClN5O5 re~uires: C, 41~.44; H,~ 5.21; N,~20.14.
Dias~tere;omer K-16: ~a]D25= +63.0 (c Q.019, MeOH)~;~ Rf 0.67; ~mp 118-120C; yield (8 g, 61.5%); 1H
;25~ NMR~ (CDC13~ 1;.16~ (t, J=7 Hz, 3H, OCH2C~3), 1.82 (s, 3H~, C-5 CH3),~ 2.30 ~(m,~lH,~ H-2'), 2.64 (m, 2H, H-2' and 5'~-OH~which~exchan~es with deuterium oxide), 3.50-3.98 (m, 5H,~ H-4', H-5',~ OC~2CH3),~ ~4.32 (m, lH, H-3'), 4.92 (s, ;lH, H-6), 5.84 ~d, ~ J1~,2~=6-0 Hz, lH, H-1'), 8.30 (s, lH, NH, exchanges with deuteri~m oxide); 13C NMR
i (CDCl3) b 14.93 (OCH2_H3), 21.76 (C-S CH3), 37.04 C-2'~, 60.10 ~C-3'),~60.94 (C-S), 62.2~ (C-5'), 65.55 (OCH2CH3)i 84.01 (C-4'), 87.04 (C-1'), 87.92 (C-6), 150.62 (C-2 C=0), 166 62~(C-4 C=0)~.
Diastereomer K-17~: [a~D25= -15.3~ (c0.028, ;~ MeOH); Rf 0.~72; oll; yield (0.5 g, 3.7%); 1H NMR

2~30Z65 WO 94/14831 PCT/~A93/00553 -13~

(CDCl3) ~ 1.10 (t, J=7 Hz, 3H, OCH2C~3), 1.68 (s, 3H, C-5 CH3), 2.10 (m, lH, H-2'), 2.78 (m, lH, H-2"), 3.40-3.92 (m, 5H, H-4', H-5', OCH2CH3), 4.36 (m, lH, H-3~), 4.48 (s, lH, H-6), 5.16 ~d, Jl',2'=6- Hz~
- lH, H-l'), 9.04 (s, lH, NH, exchanges with deuterium oxide); 13C NMR (CDCl3) ~ 14.72 (OCH2CH3), 21.58 (C-5 CH3), 34.94 (C-2'), 61.09 (C-5), 61.56 (C-3'), 62.96 10~ (C-5'), 65.50 ~O_H2CH3), 85.11 (C-4'), 92.78 (C-l'), 93.86 (C-6), 150.49 (C-2 C=0), 166.25 (C-4 C=0).
Diastereomer K-18:[a]D25= +42.1 (c 0.009, MeOH); Rf 0.61; oil; yield (3.5 g, 26.7%); lH NMR
(CDCl3) ~ 1.18 (t, J=7 Hz, 3H, OCH2CH3), 1.78 (s, 3H, C-5 CH3), 2.28 ~(m, lH, H-2'), 2.58 (m, lH, H-2"), 3.20 (br s, lH, 5'-OH, exchan~es with deuterium oxide), 3~.60-3.98 tm, ~5H,~ H-4', H-5', OC_2CH3), 4.36 tm, lH, H-3~), 4.82 (s,~ lH, H-6).~ 5-64 (d, Jl',2'=6- Hz~
lH,~H-1'~, 8.80~ (br~ s, lH, NH, exchanges with deuterium 20~ox~l~de~ 3C ~NMR~ (CDCl3) ~ 14.84~ ;tOCH~H3), 25.88 (C-~5 CH3), 36.98~ (C-2'), 60.34 (C-3') 62.16 (C-5'), 66.67 OCH2CH3~ 6~6.98; ~(C-5), 84.15 (C-4'),~ 87,88 (C-l'), 89~.~7-`9;~ C-6i,~ 151.~10~;(C-2 C=0), 167.79~(`C-4~C=0).
Schemati~ for EXamD1e 3 CI~N--H: : CI.. ~N-~ CI--~N--H
C~ EtO~ Zl, ~ E~O~N O ~ EtO ;;~N~O .

0 ~ N, Z
'xample 4 Preparation of 5;-chloro-~6-methoxy-5,6-dihydro-3'-35~ azldo-3'-deoxythymldlne.
N-Chlorosuccinimide (0.2 g, 1.5 mmol) was added ~ to a solution of 3'-azido-3~-deoxythymidine (0.2 g, 0.75 : -WO9411~1 PCT/CA93/00553 r 2~302~S ~ 14-mmol) in methanol (10 mL) and glacial acetic acid (0.6 mL) with stirring and the reaction was allowed to proceed at 25C for 15 h. At this time additional N-chlorosuccinimide (0.2 g, 1.5 mmol) and glacial acetic acid (0.6 mL) were added and the reaction was allowed to proceed at 25~C for 24 h with stirring prior to neutralization to pH 6.5 using methanolic sodium hydroxide~ Removal of the solvent in lQ vacuo gave a residue which was dissolved in chloroform (5 mL), the chloroform solution was washed with cold water (2 ~; x 5 mL), dried (Na2SO4) and the solvent was removed in vacuo. The residue obtained was purified by elution from a silica gel -column using chloroform-methanol (95:5, v/v) as eluent to yield a mixture of diastereomers (5R,6R)-5-chloro-6-methoxy-5,6-dihydro-3'-azido-3'-deoxythymidine (K-19) an~ (5S,6R)-5-chloro-6-methoxy-5,6-dihydro-3'-azido-3'-deoxythymidine (K-20). Analysis found: C, 39.46;
H, 4.87. Cl~ H~16ClN5O5 requires: C, 39~58; H, 4.83. The two ~diaste~eomers K-19 and K-20 were separated by; PTLC using~Whatman PLK5F silica gel plates (1 mM thick-`ness~using chloroform-methanol (95:5, v/v) as development solvent.
Diast~e~reomer K-~9: []D25= +74.7 (c 25~;~0~.00~38, MeOH); Rf~0~.57;~ oil; yield (0.1 g, 40%); 1H NMR
CDCl3) ~ 1.80 ~(s, 3H, C-5 CH3~, 2~30 and 2.63 (two m, lH~each, H-2'),~3~.46 (s, 3H, OCH3), 3.82 (m, lH, H-5'j, 3.96;(m, 2H,;~H-4', H-5~"), 4.32 (m, lH, H-3'), 4.90 (s, lH, H-6)~, 5.92 (d, J1~,2~=6.0 Hz, lH, H-1'), 8.80 (s, IH, NH, exchanges with deuterium oxide); 13C NMR
: .
i~ (CDCl3) b 21.60 (CH3), 36.95 (C-2'), 57.36 (OCH3), 60~.04 (C-3'), ~60.88 (C-5), 62.05 (C-5'), 83.95 (C-4'), 86.39 (C-1'), 88.62~;~(C-6), 150.66 ~C-2 C=0), 166.71 (C-4 ':: C=O).
35 ~ Diastereomer K-20: [~D25= +39 3 (c O.0059, MeOH), Rf 0.54; oil; yield (45 mg, 18%); lH NMR
(CDCl3) ~ 1.83 (s, 3H, C-5 CH3), 2.32 and 2.75 (two m, , ~'~94/1~l Z13026~ PCT/CA93/00553 ~ lH each, H-2'), 3.56 ~s, 3H, OCH3), 3.80 ~m, 1~, ~-5'), : 3.98 (m, 2H, H-4', H-5"), 4.40 (m, lH, H-3'), 4.76 (s, lH, H-6), 5.78 (d, Jli 2~=6.0 Hz, lH, H-l'), 8.28 (br s, lH, NH, exchanges with deuterium oxide); 13C NMR
(CDCl3) ~ 26.05 (CH3), 37.0 (C-2'), 58.23 (OCH3), : 60.35 lC-3'), 62.34~ (C-5'), 66.88 (C-5), 84.25 (C-4'), B8.18 (C-l'), 91.46 (C-6), 150.57 (C-2 C=0), 167.02 (C-4 , 1 0 C = O ) . : ~ :
Schematlc for Example 4 N--H O ~ N--H CI~N--H
~ : ~ ~ HOAc MeO N~O ~ MeO N
I ~ N--Ct ~ M~OH
15HO~o--J ~ ~; ~ HO~ o~J HO~

n~ K ~9 N, K`20 Example S

20~Preparat~ion ~of ~S-bromo-6:-hydroxy-5,6-dihydro-2'~,~3~ dlflehydro-2~',3'-dideoxythymidine. ::
N-Bromosucc~lnimlde (80:mg, 0.44 mmol) was added n~ allquots to ~a~:suspension~: of~:2',~3'-didehydro-2'.3'-didé~ ~ thymidi~ne~ (O.l:g,~0.44~:~mmol) ln wàter (5 mL)~ at ~0C
2:5,~ wi~t~stirring. , :~Thé~initi~al~yellow~color produced upon additlon:~of each~aliquot of~N-bromo~succinimide~disaPPeared r~apidly.~Afte~r~all ~the:N-bromosucclnlmlde had:been added.
the~ re~ac~t:ion~mixture~ was: ~sti~rred~ ~or 20 min at 0C.
Removal~o~f the~solvent~ n:~vacuo, dissolution of the residue obtalned~ in ethyl acetate (S~mL~ :adsorption onto silica :gel (l~ g), removal of the solvent in vacuo and application :of thi~s materi;al~ to~the:top of a s1llca gel~column~followed by~elution with~ chl~oroform-methanol (96:4, v/v) as eluent afforded (5R~,6R)-S-brom~-6-hydroxy-5,6-dihydro-2',3'-dideh~dro-2',3'-dideoxythymidine (K-32) and (5S.6S)-5-: : bromo-6-hydroxY-5.6-dihydro-2',3'-didehydro-2',3'-dideoxythymidine~(K-33), respectively. Analysis found: C, .

WO 94/14831 PCT/CA93l00553 ~-2~30265 - 1 6-3 7 . 8 9 ; H , 4 . 1 5 ; N , 8 . 6 3 . C 1 o H 1 3 B r N 2 5 requires: C, 37.40; H, 4.07; N, 8.72.
Diastereomer K-32: [~] D25= +31 . 9 ~c .
0. 0026, MeOH); Rf 0.42; mp 94-95C; yield ~60 mg, 43%);
lH NMR(CD30D) o 1. 88 (s, 3H, CH3), 3 . 74 ~m, 2H, H-5'), 4.80 tm, lH, H-4'), 5.15 (s, lH, H-6), 5.90 (m, lH, H-3' ),6.30 (m, lH, H-2' ), 6. 82 (m, lH, H-l ~ ); 13c ~MR
(CD30D)b 23 . 38 (CH3~), 55. 29 (C-5), 62. 56 (C-5 ' ), 81 . 76 (C-6), 87.38 (C-4'), 91.77 (C-l'), 127.14 (C-2'), 135.35 ( C- 3 ' ) .
Di as te reomer K- 3 3: E a] D2 5 = - 3 2 . 7 ( c .
0~.0011, MeOH), Rf 0.35; oil; yi ld (47 mg, 33.1%); lH
NMR (CD30D) o 1.82 (s, 3H, CH3), 3.74 (m, 2H, H-5' ), 4.75 (m, lH, H-4'), 5.28 (s, lH, H-6), 5.95 (m, lH, H-3'), 6. 24 (m, lH, H-Z' ),6.78 (m, lH, H-l ~ ); 13c NMR
(CD30D) o 23 . 30 ~ (CH3), 54 . 68 (C-5), ~ 65 . 07 (C-5 ' ), 80 .12 (C-6), 87 . 71 (C-4 '~), 90 . 79 (C-l ' ), 127 . 80 (C-2 ' ), 133 . 96 (C-3~ ,152.87 ~ C-2~ C=O), 169.92 (C-4 C=O) .
S chematlc f or Example 5 Schematic for ExamPle 5 Me~ N--H ~ 3r~N--H Bt~N--H
; 25 ~ N~bO ff' ~ HO~N~O H
HO~J ~ HO~ HO~

K 32 ~ 33 3~0 ~ Example 6 : ~
Illustrates: the preparation of 5-halo-6-alkoxy-~ ~ .
5,~6- dihydrothymidines following the alternate method of preparation seen i~D example 5 and descri~ed in the ::35 ::schematic for Example~6.~
.:

~ .
:

v~ln 94114831 2~l3026S PCTJCA93JOV553 Schematic f or ExamDle 5 S
Schematic for ExamPle 6 --H U~
R,--H . ~N Rj ~o ~ X---Y X--Y

x~ tSR 6R) 155 65) ~55 6R) Starting from :the appropriately substi~uted compounds of 15 ~formula (II), o~f formula (:IV) and of formula ~V), the following compounds of the formula ~I) are pre~ared:
::: : : : :

~20 30~
': 1 ~ ~ /, ;

:: /

: ~ :

, WO 94/14~ J PCl`/CA931005~3 2~30Z65 ~ ~ ~ d d `d d d -d d ,, d d d :r: ~ '~ ~~ ~ c u~ ~ O
~ o o o o o o o ~ .
t~ o o o z O O O O az z C: .~ :
U~ o o o , o Z
r~ ~ ~D ~ ~ O
_ ~ ~ r , I + + ~-. u u u u ~-r~ ~ D ~ D~ ~ .
C) C::: O O O Z O O O O O O O
~ ~ i O~ ~ ~ ~ ~ ~ : L ~ ~ ~
~: ~ 5 ~:
8 ~ ~
~: ~ ~:

~- _ ~-1 g O C~ .
G : ~ ~ ~ ~ o ~ ~ ~:
: Q ~ ~ ~'`1 t~ ~ ~ N t~ ~ :
g z ~ o W ~ : ~ ~ . ~'.

Q ~ "

: 5'~ ~ ~
: ! ~ ,- ,` ~ ,.
~ N N

U~ ~ D ~D ~ ~ ,n ~ ; ~o u. U~ r r ` U~r r ~

~ ~ e e ~ 3 e e ~ ~3 ~ ~d ~
: ~ ~ ~ ~ ~ ~ ~
~ U _ _ ~ ~ _ _ _ _ _ ~ _~ o :~ . ~ C~ lq ~ ~
SUBSTITlJTE~ SHEET

wn 94/1~1 2 ~ 3 0 2 6 5 PCTICA93/00553 Example 7 .

Preparation of 5-bromo-6-azido-5,6-dihydro-3'-azido-3'-deoxythymidine.
N-Bromosuccinimide (36 mg, 2 mmol) was added in aliquots to a precooled (-5C) suspension prepared by mix-ing a solution of 3'-azido-3'-deoxythymidine (52 mg, 2 mmol) in dimethoxyethane (10 ~L) and a solution of sodium azlde (52 mg, 8 mmol) in water (0.125 mL) with stirring.
The initial yellow; color produced upon addition of each aliguot of N bromosuccinimide quickly disappeared. When alI the N-bromosuccinimide had rea~ted, the reaction mixture was stirred for 30 min at 0C, poured onto ice-water (25 mL) and extracted with ethyl acetate (3 X 50 mL).
. ~ ~
Washlng the ethyl~ acetate extract with cold water (10 mL), drying the `ethyl~ acetate solution (Na2SO4) and removal of the solvent in;~vacuo gave~a residue which was separated by~;silica~gel ~column~ chromatography using chlorofrom as eluent ~to give a~mlxture of diastereomers ~5R,6R)-5-bromo-6-azido-5,6-dihydro-3'-azido-3'-deoxythymidine (K-34), (5~S,6S)-5-bromo-6~-azido-5,6-dihydro-3'-azido-3'-deoxyth ~ dine ~K-35), ~and ~5R,6S~)-5-bromo-6~azido-5,6-25~ dihydro-3'-azido-3'-deoxythymidine (K 36), respectively.
AD~a1YS~i9 found:~C~, 30.69; H, 3.95; N, 28.77.
C1~oH13BrNgO4 re~ulres: C, 30.86; H, 3.36; N, 28.79.
Diastereomers K-34 and K-35: Rf 0.63; yield (30 mg, 38.6%); 1H NMR~CDCl3) b 1.98 and 2.0 ~two s, 3H
total, iCH3), 2.30-2.74 (m, 2H total, H-2'), 2.94 (br s, lH, 5'-OH, exchhnge~s~ with deuterium oxide), 3.82-4.02 (m, 3H total, H-4' and H-5'), 4.30 and 4.36 (two m, lH total, H-3'), 5.42 and 5.64 (two s, lH total, H-6), 5.76 and 6.20 ~two d, J1~,2~=6.~0 Hz, lH total, H-1'), 8.60 and 8.68 (two s, lH total, NH, exchanges with deuterium oxide);
3C NMR (CDCl3) ~ 22.76 and 23.08 (CH3), 35.99 and .
:

WO 94/1483l PCT/CA93/00553 ;23l30Z~;5 -20-36.71 ~C-2' ), 52.31 and 52.79 (C-5), 60.04 and 60 52 (C-6), 61.72 and 62.35 (C-5 ' ), 73 . 88 and 76 . 64 (C-3 ' ), 83 . 78 and 84 . 22 (C-4 ' ), 87 . 81 (C-l ' ), 149.88 and 150 . 02 (C-2 C=0), 166.11 (C-4 C=0) .
Diastereomer K-36: ~a] D25= -47 . 5~ (c .
~; 0.0016, MeOH); Rf 0.61, yield (20 mg, 25.7%); lH NMR
(CDCl3) ~ 1.98 (s, 3H, CH3), 2.24 and 2.34 (two m, lH
10 each, H-2 ' ), 3.82-4.05 (m, 3H, H-4 ', H-5 ' ), 4 . 37 (m, lH, H-3' ), 5.74 (s, lH, :: H-6), 6.04 (d- Jl' ,2'=6 0 Hz~
lH, H-l' ), 8. 25 (s,: ~ lX, NH, exchanges with deuterium oxide); 13c NMR (CDCl3) ~ 27 . 63 (CH3), 36 . 02 : (C-2 ' ), 60 . 98 (~-6), 61 . 75 (C-5), 62. 65 (C-5 ~ ), 7d2.75 (C-3 ' ), 83 . 56 (C-4 ' ), 85 . 05 (C-l ' ), 149. 66 (C-2 C=0), 166~. 26 (C-4 C=0) .
Schematic for Example 7 ~mati~ for ExamDle 7 2 0 ~ ~H ~ O ~ Br~N--H B~ H ar XI~N--H

~ ~ NaN~ N~ t~o ~;;l ~ H, O ~ HO~---o~J i HO~ O i ~--~o~

tl~ VI ~ J~ ~IS ~J~ ~36 Example 8 Illustrates~ the~ preparation of 5-halo-6-azido-5~,6- dlhydrothymldines~ using a procedure similar to the one 30 outllned in Example 7. ~Starting from the appropriately substituted compounds of formula (II), formula (V) and formula (VI), the ~following compounds are prepared:

::: : :
:~ 3 5 ~ ~

;: ~

W() 94114831 Z~30265 PCT/CA~3/00553 . I ~ 'o 'o 'o 'o 'o 'o 'o -o 'o, -.~
. ~ ~ U~ p D D _ D D- ^ D D D
~ 7 !~ ooooooooo ,~ 1 ~ ~ ~ ~ .
V : ~ :~ ~ y x~ ~ ~ æ: z Z ~ Z ~ ~ ~ a : a~ a a a ~ ~ . I
~:: ' :0~ : ~
,, : ~ ~ Z ~ Z Z Z ~ Z Z Z Z
~: ~
v, ~ ~ w~ m a~ ~ ~

~ N N

'~ ~ , ~D : ,~ ~ ~
:~ ~ N g ~ D 5~
.

~: ~N~ N '1 t~ N i_ ;~ D I ~
o o ~oi ~ ~
~ ~ y y ~ Y ~ ' o~ ~

~ ~: _ ~ ~ _ _ _ _ ~ _ ~
g ~ U!

:
2~1JBST~TUTE~ SHE~T

WO~4tl~1 pcTlcA93looss3 ...

2 ~ 30 2 6 ~ -22-The compounds listed in the Examples, Tables I, II, and III have been found to have anti-human immunodeficiency virus properties.
1, Anti-human immunodeficiency activity.
The test is designed to measure the efficacy against HIV ~or drugs acting at any stage of the virus reproductive cycle and involves the killing of T4 lq lymphocytes by HIV.
: In order to test the activity of the compounds according to the invention, all tests were compared with a~
: least.one positive (e,g, AZT-treated) control done at the same time under identical conditions, 15The test drug is dissolved in dimethylsulfoxide, then diluted 1:100 in cell culture medium before preparing ~ ~serial half-loglo dilutions, T4 lymphocytes (CEM cell :~: : line) are added and :after a hrief in~erval HIV-1 is added, ~ , ~: ~ : resulting in a~ 200 final dilution of the test drug.
20~Uninfected ~cells~ wl~th ~the test drug serve as a toxicity control, and:infected and uninfected cells without the test , ~
drug ~serve as basic :controls. Cultures are incubated at 37C in a ~5% CO2~:at sphere for 6 days. The tetrazolium salt, XTT,:is ad~ed~to all:wells, and cultures are incubat-25 :ed~;to ~allow formazan color development by viable cells.
Indlvldual wells~ are~ a~al~zed spectrophotometrically to quantitate formazan production, and in addition are viewed microscoplcally:~for detectlon:of vlable cells and conflrm-ation of~ protective actlvity. Tes,t drug-treated virus~
:~30 infe~ted ceIls~ are compared with test drug-treated non-infected cells and with other appropriate controls ~;(untreated infect~d and untreated noninfected cells, test drug-containing wells without cells, etc.) on the same : : plate ~see O.W. Weislow, R. Kiser, D. Fine, J. Bader, R.H.
Shoem ker, M.R.~ Boyd, J. Natl. Cancer Inst., 81 , 577 (1989)J. The:test results are shown in the following Table IV, the compounds llsted being comparable to 3'-azido-3'-!~0 ~4/1~,1 PCT/CA93/00553 ~3 2~30;~6S
TABLE (IV) Arsti-~V activi~ of 5-halo-6-all;oxy ~or azido)-5~6-dihydrothymidinc diaslereomers tesled . _ .. .. . _ . _ .. .
Substance ICso(M) ECs~(M) Ti(so(lCsolEc~o) K-l 1.72 x 10' 3.27 x 109 5260 K-2 4.25 x lOs 2.80x 10' 152 K-3 1.85 x 10-~ 6.75 x 109 2740 K 4 2.22 x 10 ' 2.37 x 10~ 936 K-10 1.72 x 10~ 5.25 x 109 328 K-II 9.72 x 10~ 3.25 x 109 2991 .-12/}C 13d >1.28 x iO 5.46 x 10 K-14/K-15~ >1.40x 10' ND' NDK-19/lC-20d >8.98 x 10~ 5.79 x 10~ 155 K-21 1.87 x lOs 3.17 x 109 5899 ~` K-22 6.42 x 10~ 5.15 x 109 1247 K-23 >g.O x 10~ 5.55 x lO~ 144 K-25 >8.0 x 10~ 3.79 x 105 21 K-26 ~5.73 x lo5 ~ ;; ND ND
K-27 1.22 x lO~ 3.75 x l09 3253 K-281K-29d ~1.03 x 11, ' 3.75 x IOJ 2 .-30/iC-31d 6.60 x tO 3.75 x 10 178 K-32 ~ >2.0 x 10~ ~ ND ND
-33 2.0~x 10' ~ ~ ND ND
K-34/1;-35d 1.76 x 10~ ~ ~ ND NDIC-37/~-381K-3g/lC-4~ 3.5 x 10 ~ ~ ~ 1.49 x 10 235 K411K42hC43d ~ ~l.o~x~ : : 1.45 ~5 10~ 6896 44 4.47 x~10-S ~ 9.18 x l07 49 AZI' 5; X 10~ ~3 x ~09 - .-- . ... . . . ~ ... _................. _ 'lltc ICso value is the tcst drug conctntralion which results in a SOD/o survival of uninfccted control cells ~cg. cvtotoxic activi~ of tne lest drug) ~Ihe EC50 value is the test drug concentra ion which produces a 50~/0 su vival of HIV infectcd cells rtlative IO
uninfected controls ~eg. in vitro anti-HlV activity) Ibe~apeutic index ested as a mixturc of diastereomers ~ND = not detcrmined ST~TU~E:SHEET

Claims (56)

We claim:

1. A dihydrothymidine derivative of the formula (I):

(I) or a non-toxic pharmaceutically acceptable salt thereof, wherein R1 is a halogen substituent selected from the group consisting of iodo, bromo, chloro and fluoro; R2 is a member selected from the group consisting of alkoxy wherein the alkyl moiety is a straight or branched chain having from 1 to 16 carbon atoms, hydroxy and azido; and X-Y is a member selected from the group consisting of CH(N3)-CH2, CH(F)-CH2 and CH=CH.

2. A dihydrothymidine derivative according to Claim 1, wherein R2 is a methoxy.

3. A dihydrothymidine derivative according to Claim 1, wherein R2 is an ethoxy.

4. A dihydrothymidine derivative according to Claim 1, wherein R2 is an isopropoxy.

5. A dihydrothymidine derivative according to Claim 1, wherein R2 is a 1-octyloxy.

6. A dihydrothymidine derivative according to Claim 1, wherein R2 is a 1-hexadecyloxy.

7. A dihydrothymidine derivative according to Claim 1, wherein R2 is a hydroxy or an azido.

8. (5R,6R)-5-bromo-6-methoxy-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 2.

9. (5S,6S)-5-bromo-6-methoxy-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 2.

10. (5R,6R)-5-bromo-6-methoxy-5,6-dihydro-3'-fluoro-3'-deoxythymidine according to Claim 2.

11. (5S,6S)-5-bromo-6-methoxy-5,6-dihydro-3'-fluoro-3'-deoxythymldine according to Claim 2.

12. (5R,6R)-5-bromo-6-methoxy-5,6-dihydro-2',3'-didehydro-2',3'-dideoxythymidine according to Claim 2.

13. (5S,6S)-5-bromo-6-methoxy-5,6-dihydro-2',3'-didehydro-2',3'-dideoxythymidine according to Claim 2.

14. (5R,6R)-5-chloro-6-methoxy-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 2.

15. (5S,6R)-5-chloro-6-methoxy-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 2.

16. (5R,6R)-5-iodo-6-methoxy-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 2.

17. (5S,6S)-5-iodo-6-methoxy-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 2.

18. (5R,6R)-5-chloro-6-methoxy-5,6-dihydro-3'-fluoro-3'-deoxythymidine according to Claim 2.

19. (5S,6S)-5-chloro-6-methoxy-5,6-dihydro-3'-fluoro-3'-deoxythymidine according to Claim 2.

20. (5S,6R)-5-chloro-6-methoxy-5,6-dihydro-3'-fluoro-3'-deoxythymidine according to Claim 2.

21. (5R,6R)-5-iodo-6-methoxy-5,6-dihydro-3'-fluoro-3'-deoxythymidine according to Claim 2.

22. (5S,6S)-5-iodo-6-methoxy-5,6-dihydro-3'-fluoro-3'-deoxythymidine according to Claim 2.

23. (5R,6R)-5-chloro-6-methoxy-5,6-dihydro-2',3'-didehydro-2',3'-dideoxythymidine according to Claim 2.

24. (5S,6S)-5-chloro-6-methoxy-5,6-dihydro-2',3'-didehydro-2',3'-dideoxythymidine according to Claim 2.

25. (5R,6R)-5-iodo-6-methoxy-5,6-dihydro-2'-3'-didehydro-2',3'-dideoxythymidine according to Claim 2.

26. (5S,6S)-5-iodo-6-methoxy-5,6-dihydro-2',3'-didehydro-2',3'-dideoxythymidine according to claim 2.

27. (5R,6R)-5-bromo-6-ethoxy-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 3.

28. (5S,6S)-5-bromo-6-ethoxy-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 3.

29. (5R,6R)-5-bromo-6-ethoxy-5,6-dihydro-2',3'-didehydro-2',3'-dideoxythymidine according to Claim 3.

30. (5S,6S)-5-bromo-6-ethoxy-5,6-dihydro-2',3'-didehydro-2',3'-dideoxythymidine according to Claim 3.

31. (5R,6R)-5-chloro-6-ethoxy-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 3.

32. (5S,6S)-5-chloro-6-ethoxy-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 3.

33. (5S,6R)-5-chloro-6-ethoxy-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 3.

34. (5R,6R)-5-bromo-6-isopropoxy-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 4.

35. (5R,6R)-5-chloro-6-isopropoxy-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 4.

36. (5R,6R)-5-bromo-6-(1-octyloxy)-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 5.

37. (5R,6R)-5-chloro-6-(1-octyloxy)-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 5.

38. (SR,6R)-5-bromo-6-(1-hexadecyloxy)-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 6.

39. (SR,6R)-5-bromo-6-hydroxy-5,6-dihydro-2',3'-didehydro-2',3'-dideoxythymidine according to Claim 7.

40. (5S,6S)-5-bromo-6-hydroxy-5,6-dihydro-2',3'-didehydro-2',3'-dideoxythymidine according to Claim 7.

41. (5R,6R)-5-bromo-6-azido-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 7.

42. (5S,6S)-5-bromo-6-azido-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 7.

43. (5R,6S)-5-bromo-6-azido-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 7.

44. (5R,6R)-5-chloro-6-azido-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 7.

45. (5S,6S)-5-chloro-6-azido-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 7.

46. (5S,6R)-5-chloro-6-azido-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 7.

47. (5R,6S)-5-chloro-6-azido-5,6-dihydro-3'-azido-3'-deoxythymidine according to Claim 7.

48. (5R,6R)-5-bromo-6-azido-5,6-dihydro-3'-fluoro-3'-deoxythymidine according to Claim 7.

49. (5S,6S)-5-bromo-6-azido-5,6-dihydro-3'-fluoro-3'-deoxythymidine according to Claim 7.

50. (5R,6S)-5-bromo-6-azido-5,6-dihydro-3'-fluoro-3'-deoxythymidine according to Claim 7.

51. (5R,6R)-5-bromo-6-azido-5,6-dihydro-2',3'-didehydro-2',3'-dideoxythymidine according to Claim 7.

52. (5S,6S)-5-bromo-6-azido-5,6-dihydro-2',3'-didehydro-2',3'-dideoxythymidine according to Claim 7.

53. A method of preparing 5-halo-6-alkoxy-5,6-dihydro-thymidine derivatives of formula (I) as in Claim 2 or 3 or 4 or 5 or 6:

(I) wherein R1 is a iodo, bromo, chloro or fluoro atom; R2 represents a C1-C16 alkoxy group with a straight or branched alkyl chain and X-Z is CH=CH, CH(N3)-CH2 or CH(F)-CH2 which comprises:
reacting a thymidine compound of formula (II):
(II) with an electrophilic source of halogen of formula (III) wherein R1 is as defined above and Z is independently a iodo, bromo or chloro atom.
In the presence of an alkyl alcohol of the formula (IV):

wherein R2 is as defined above.

54. A method of preparing dihydrothymidine derivatives according to Claim 53, wherein the electropholic source of halogen is:
(V) wherein R1 is a iodo, bromo or chloro atom.

55. A method of preparing 5-halo-6-azido-5,6-dihydro-thymidine derivatives of formula (I) as in claim 7:
(I) wherein R1 is a iodo, bromo, chloro or fluoro atom; R2 is an azido group; and X-Z is CH=CH, C H ( N 3 ) - C H 2 or CH(F)-C which comprises:
reacting a thymidine of formula (II) (II) with an electrophilic source of halogen of formula (III):

wherein Z is independently a iodo, bromo or chloro atom and R1 is as defined above.
In the presence of an alkali metal azide of the formula (VI):

wherein R2 is as defined above and M is a sodium, selected from the group of sodium, lithium and potassium.

56. A method of preparing 5-halo-6-hydroxy-5,6-dihydro-thymidine derivatives of formula (I) as in claim 7:
(I) wherein R1 is a iodo, bromo, chloro or fluoro atom; R2 is a hydroxy radical; and X-Z is CH=CH, C H ( N 3 ) -CH2 or CH(F)-C which comprises:
reacting a thymidine of formula (II):

(II) with an electrophilic source of halogen of formula (III):

wherein Z is independently a iodo, bromo or chloro atom and R1 is as defined above.

In the presence of a solvent of formula (IV):

wherein R2 is an hydroxy group.